In women, gynecologic cancers account for more than one-fourth of the malignancies.
For example, endometrial cancer occurs at a rate of approximately 44,500 new cases per year with approximately 10,000 deaths per year. If diagnosed and treated early, when the cancer is still confined to the endometrium, cure can be achieved in approximately 95% of the cases by hysterectomy. Pap smears can show endometrial cancers but are effective in only 50% of the cases. For the remainder, abnormal vaginal bleeding is typically the first clinical sign of endometrial cancer.
Sarcoma of the uterus, a very rare kind of cancer in women, is a disease in which cancer (malignant) cells start growing in the muscles or other supporting tissues of the uterus. Sarcoma of the uterus is different from cancer of the endometrium, a disease in which cancer cells start growing in the lining of the uterus. Women who have received therapy with high-dose x-rays (external beam radiation therapy) to their pelvis are at a higher risk to develop sarcoma of the uterus. These x-rays are sometimes given to women to stop bleeding from the uterus. Like most cancers, sarcoma of the uterus is best treated when it is found (diagnosed) early. Sarcoma of the uterus usually begins after menopause. When a patient has signs of such cancer, an internal pelvic examination is usually performed to detect any lumps or changes in shape of the pelvic organs. A Pap test may also be performed, however because sarcoma of the uterus begins inside the organ, this cancer is not usually detected by the Pap test. A dilation and curettage (D&C) may also be performed and a biopsy sample taken and examined microscopically.
It is estimated that one of every nine women in America will develop breast cancer sometime during her life based on a lifespan of 85 years. Annually, over 180,000 women in the United States are diagnosed with breast cancer and approximately 46,000 die from this disease. Every woman is at risk for breast cancer. However, a woman's chances of developing breast cancer increase as she grows older; 80 percent of all cancers are found in women over the age of 50. There are also several risk factors that can increase a woman's chances of developing breast cancer. These include a family history of breast cancer, having no children or the first child after the age of 30, and an early start of menstruation. However, more than 70 percent of women who develop breast cancer have no known risk factors. Less than 10 percent of breast cancer cases are thought to be related to the BRCA1 gene discovered in 1994. Researchers are now investigating the role of other factors such as nutrition, alcohol, exercise, smoking, and oral contraceptives in development of this gynecologic cancer. Mammograms, or special x-rays of the breast, can detect more than 90 percent of all cancers.
Carcinoma of the ovary is another very common gynecologic cancer. In fact, ovarian cancer causes more deaths than any other cancer of the female reproductive system. Approximately one in 70 women develop ovarian cancer during their lifetime. An estimated 14,500 deaths in 1995 resulted from ovarian cancer. Ovarian cancer often does not cause any noticeable symptoms. Possible warning signals include an enlarged abdomen due to an accumulation of fluid or vague digestive disturbances (discomfort, gas or distention) in women over 40. In rare cases abnormal vaginal bleeding also occurs. Pap tests do not detect ovarian cancer. Thus, periodic, complete pelvic examinations are important and recommended annually for women over 40.
In all of these gynecologic cancers, chances of survival are much better if the cancer is diagnosed at an early stage. Further, treatment decisions for the individual are linked to the stage of the cancer present in that individual. However, current cancer staging methods are limited and some such cancers initially staged as not metastatic are actually metastatic. Discovery of metastasis is significant because patients with metastatic cancers have a poorer prognosis and require significantly different therapy than those with localized cancers.
Accordingly, there is a great need for sensitive and accurate methods for early detection and staging of gynecologic cancers such as endometrial, breast, uterine and ovarian cancer in a human to determine whether or not such cancer has metastasized and for monitoring the progress of such cancer in a human which has not metastasized for the onset of metastasis.
Steroid binding proteins, including uteroglobin and CC10, are a class of proteins which bind steroids along with methylsulfonyl metabolites of polychlorinated biphenyls. The exact function of members of this class of protein is uncertain. However, uteroglobin has been shown to inhibit PLA2 mediated responses.
Gene and gene products homologous to uteroglobin are described in WO 97/34997 entitled Human Endometrial Specific Steroid Binding Factors I, II and III. The genes and their encoded products are referred to as Human Endometrial Specific Steroid-Binding Factors I, II and III (hESF I, II, and III). Methods for utilizing these genes and gene products in research and diagnostic and clinical arts are disclosed. In particular, methods for detecting mutations in the hESFI, II or III gene or altered protein expression resulting from a mutant gene are indicated to be useful in diagnosing susceptibility to asthma and endometrial cancer.
A gene and gene product homologous to uteroglobin and very similar to hESF III, referred to as human mammoglobin homolog or HGH, is also described in WO 99/19487. The human mammoglobin homolog is suggested to be useful for the diagnosis, prevention and treatment of neoplastic disorders and endometriosis.
It has now been found that detection of hESF III, referred to herein as ESBPIII, is useful in diagnosing, monitoring, staging, prognosticating, imaging and treating cancers, particularly gynecologic cancers including endometrial, mammary, ovary and uterine cancer.
Accordingly, in the present invention, methods are provided for detecting, diagnosing, monitoring, staging, prognosticating, imaging and treating gynecologic cancers via ESBPIII. ESBPIII refers, among other things, to native protein expressed by the gene comprising the polynucleotide sequence of SEQ ID NO:1. The amino acid sequence of a polypeptide encoded by SEQ ID NO:1 is depicted herein as SEQ ID NO:2. In the alternative, what is meant by the ESBPIII as used herein, means the native mRNA encoded by the gene comprising the polynucleotide sequence of SEQ ID NO:1 or levels of the gene comprising the polynucleotide sequence of SEQ ID NO:1.
Other objects, features, advantages and aspects of the present invention will become apparent to those of skill in the art from the following description. It should be understood, however, that the following description and the specific examples, while indicating preferred embodiments of the invention are given by way of illustration only. Various changes and modifications within the spirit and scope of the disclosed invention will become readily apparent to those skilled in the art from reading the following description and from reading the other parts of the present disclosure.